tbuckley/cabot-search huggingface dataset:
An H<sub>2</sub>S‐BMP6 Dual‐Loading System with Regulating Yap/Taz and Jun Pathway for Synergistic Critical Limb Ischemia Salvaging Therapy
Authors: Jiateng Hu, Zhijue Xu, Donghui Liao, Yihong Jiang, Hongji Pu, Zhaoyu Wu, Xintong Xu, Zhen Zhao, Jianqiang Liu, Xinwu Lu, Xiaobing Liu, Bo Li
Journal: Advanced Healthcare Materials (2023)

Critical limb ischemia, the final course of peripheral artery disease, is characterized by an insufficient supply of blood flow and excessive oxidative stress. H2 S molecular therapy possesses huge potential for accelerating revascularization and scavenging intracellular reactive oxygen species (ROS). Moreover, it is found that BMP6 is the most significantly up-expressed secreted protein-related gene in HUVECs treated with GYY4137, a H2 S donor, based on the transcriptome analysis. Herein, a UIO-66-NH2 @GYY4137@BMP6 co-delivery nanoplatform to strengthen the therapeutic effects of limb ischemia is developed. The established UIO-66-NH2 @GYY4137@BMP6 nanoplatform exerts its proangiogenic and anti-oxidation functions by regulating key pathways. The underlying molecular mechanisms of UIO-66-NH2 @GYY4137@BMP6 dual-loading system lie in the upregulation of phosphorylated YAP/TAZ and Jun to promote HUVECs proliferation and downregulation of phosphorylated p53/p21 to scavenge excessive ROS. Meanwhile, laser-doppler perfusion imaging (LDPI), injury severity evaluation, and histological analysis confirm the excellent therapeutic effects of UIO-66-NH2 @GYY4137@BMP6 in vivo. This work may shed light on the treatment of critical limb ischemia by regulating YAP, Jun, and p53 signaling pathways based on gas-protein synergistic therapy.
Stowaways in the cargo: Contaminating nucleic acids in rAAV preparations for gene therapy
Authors: Mark A. Brimble, Stephen M. Winston, Andrew M. Davidoff
Journal: Molecular Therapy (2023)

Recombinant AAV (rAAV) is the most used delivery vector for clinical gene therapy. However, many issues must be addressed before safer and more widespread implementation can be achieved. At present, efficacies are highly variable across trials and patients, and immune responses after treatment are widely reported. Although rAAV is capable of directly delivering gene-encoded therapeutic sequences, increased scrutiny of viral preparations for translational use have revealed contaminating nucleic acid species packaged within rAAV preparations. The introduction of non-therapeutic nucleic acids into a recipient patient adds to the risk burden, immunogenic or otherwise, of rAAV therapies. DNA from incomplete expression cassettes, portions of plasmids or vectors used to facilitate viral replication, and production cell line genomes all have the potential to be packaged within rAAV. Here, we review what is currently known about the profile, abundance, and post-treatment consequences of nucleic acid impurities within rAAV and cover strategies that have been developed to improve rAAV purity. Furthering our understanding of these aberrantly packaged DNA species will help to ensure the continued safe implementation of rAAV therapies as the number of patients treated with this modality increases.
Antipsychotic drug prescribing and mortality in people with dementia before and during the COVID-19 pandemic: a retrospective cohort study in Wales, UK
Authors: Christian Schnier, Aoife McCarthy, Daniel R Morales, Ashley Akbari, Reecha Sofat, Caroline Dale, Rohan Takhar, Mamas A Mamas, Kamlesh Khunti, Francesco Zaccardi, Cathie LM Sudlow, Tim Wilkinson
Journal: The Lancet Healthy Longevity (2023)

Concerns have been raised that antipsychotic drug prescribing, which has been associated with increased mortality in people with dementia, might have increased during the COVID-19 pandemic due to social restrictions imposed to limit the spread of SARS-CoV-2. We used multisource, routinely collected health-care data from Wales, UK to investigate prescribing and mortality variations in people with dementia before and during the COVID-19 pandemic.
Pharmacokinetics, safety, and tolerability of dispersible and immediate-release abacavir, dolutegravir, and lamivudine tablets in children with HIV (IMPAACT 2019): week 24 results of an open-label, multicentre, phase 1–2 dose-confirmation study
Authors: Kristina M Brooks, Jennifer J Kiser, Lauren Ziemba, Shawn Ward, Yasha Rani, Tim R Cressey, Gaerolwe R Masheto, Haseena Cassim, Jaime G Deville, Ponego L Ponatshego, Faeezah Patel, Linda Aurpibul, Shaun L Barnabas, Iris Mustich, Anne Coletti, Barbara Heckman, Chelsea Krotje, Mark Lojacono, Dwight E Yin, Ellen Townley, Jack Moye, Sai Majji, Edward P Acosta, Kevin Ryan, Hardik Chandasana, Cynthia H Brothers, Ann M Buchanan, Helena Rabie, Patricia M Flynn
Journal: The Lancet HIV (2023)
Effectiveness of bivalent mRNA vaccines against medically attended symptomatic SARS-CoV-2 infection and COVID-19-related hospital admission among SARS-CoV-2-naive and previously infected individuals: a retrospective cohort study
Authors: Celine Y Tan, Calvin J Chiew, Deanette Pang, Vernon J Lee, Benjamin Ong, Lin-Fa Wang, Ee Chee Ren, David Chien Lye, Kelvin Bryan Tan
Journal: The Lancet Infectious Diseases (2023)
Mortality rates among patients successfully treated for hepatitis C in the era of interferon-free antivirals: population based cohort study
Authors: Victoria Hamill, Stanley Wong, Jennifer Benselin, Mel Krajden, Peter C Hayes, David Mutimer, Amanda Yu, John F Dillon, William Gelson, Hector A Velásquez García, Alan Yeung, Philip Johnson, Stephen T Barclay, Maria Alvarez, Hidenori Toyoda, Kosh Agarwal, Andrew Fraser, Sofia Bartlett, Mark Aldersley, Andy Bathgate, Mawuena Binka, Paul Richardson, Joanne R Morling, Stephen D Ryder, Douglas MacDonald, Sharon Hutchinson, Eleanor Barnes, Indra Neil Guha, William L Irving, Naveed Z Janjua, Hamish Innes
Journal: BMJ (2023)

Abstract Objectives To quantify mortality rates for patients successfully treated for hepatitis C in the era of interferon-free, direct acting antivirals and compare these rates with those of the general population. Design Population based cohort study. Setting British Columbia, Scotland, and England (England cohort consists of patients with cirrhosis only). Participants 21 790 people who were successfully treated for hepatitis C in the era of interferon-free antivirals (2014-19). Participants were divided into three liver disease severity groups: people without cirrhosis (pre-cirrhosis), those with compensated cirrhosis, and those with end stage liver disease. Follow-up started 12 weeks after antiviral treatment completion and ended on date of death or 31 December 2019. Main outcome measures Crude and age-sex standardised mortality rates, and standardised mortality ratio comparing the number of deaths with that of the general population, adjusting for age, sex, and year. Poisson regression was used to identify factors associated with all cause mortality rates. Results 1572 (7%) participants died during follow-up. The leading causes of death were drug related mortality (n=383, 24%), liver failure (n=286, 18%), and liver cancer (n=250, 16%). Crude all cause mortality rates (deaths per 1000 person years) were 31.4 (95% confidence interval 29.3 to 33.7), 22.7 (20.7 to 25.0), and 39.6 (35.4 to 44.3) for cohorts from British Columbia, Scotland, and England, respectively. All cause mortality was considerably higher than the rate for the general population across all disease severity groups and settings; for example, all cause mortality was three times higher among people without cirrhosis in British Columbia (standardised mortality ratio 2.96, 95% confidence interval 2.71 to 3.23; P&lt;0.001) and more than 10 times higher for patients with end stage liver disease in British Columbia (13.61, 11.94 to 15.49; P&lt;0.001). In regression analyses, older age, recent substance misuse, alcohol misuse, and comorbidities were associated with higher mortality rates. Conclusion Mortality rates among people successfully treated for hepatitis C in the era of interferon-free, direct acting antivirals are high compared with the general population. Drug and liver related causes of death were the main drivers of excess mortality. These findings highlight the need for continued support and follow-up after successful treatment for hepatitis C to maximise the impact of direct acting antivirals.
Serial Sampling of the Small Airway Epithelium to Identify Persistent Smoking-dysregulated Genes
Authors: Yael Strulovici-Barel, Mahboubeh R. Rostami, Robert J. Kaner, Jason G. Mezey, Ronald G. Crystal
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

The small airway epithelium (beyond the sixth generation), the initiation site of smoking-induced airway disorders, is highly sensitive to the stress of smoking. Because of variations over time in smoking habits, the small airway epithelium transcriptome is dynamic, fluctuating not only among smokers but also within each smoker.
Association between antenatal corticosteroids and risk of serious infection in children: nationwide cohort study
Authors: Tsung-Chieh Yao, Sheng-Mao Chang, Chi-Shin Wu, Yi-Fen Tsai, Kun-Hua Sheen, Xiumei Hong, Hui-Yu Chen, Ann Chen Wu, Hui-Ju Tsai
Journal: BMJ (2023)

To investigate the associations between exposure to antenatal corticosteroids and serious infection in children during the first three, six, and 12 months of life. Nationwide cohort study. National Health Insurance Research Database, Birth Reporting Database, and Maternal and Child Health Database, 1 January 2008 to 31 December 2019, to identify all pregnant individuals and their offspring in Taiwan. 1 960 545 pairs of pregnant individuals and their singleton offspring. 45 232 children were exposed and 1 915 313 were not exposed to antenatal corticosteroids. Incidence rates were estimated for overall serious infection, sepsis, pneumonia, acute gastroenteritis, pyelonephritis, meningitis or encephalitis, cellulitis or soft tissue infection, septic arthritis or osteomyelitis, and endocarditis during the first three, six, and 12 months of life in children exposed versus those not exposed to antenatal corticosteroids. Cox proportional hazards models were performed to quantify adjusted hazard ratios with 95% confidence intervals for each study outcome. The study cohort was 1 960 545 singleton children: 45 232 children were exposed to one course of antenatal corticosteroids and 1 915 313 children were not exposed to antenatal corticosteroids. The adjusted hazard ratios for overall serious infection, sepsis, pneumonia, and acute gastroenteritis among children exposed to antenatal corticosteroids were significantly higher than those not exposed to antenatal corticosteroids during the first six months of life (adjusted hazard ratio 1.32, 95% confidence interval 1.18 to 1.47, P<0.001, for overall serious infection; 1.74, 1.16 to 2.61, P=0.01, for sepsis; 1.39, 1.17 to 1.65, P<0.001, for pneumonia; and 1.35, 1.10 to 1.65, P<0.001, for acute gastroenteritis).Similarly, the adjusted hazard ratios for overall serious infection (P<0.001), sepsis (P=0.02), pneumonia (P<0.001), and acute gastroenteritis (P<0.001) were significantly higher from birth to 12 months of life. In the sibling matched cohort, the results were comparable with those observed in the whole cohort, with a significantly increased risk of sepsis in the first six (P=0.01) and 12 (P=0.04) months of life. This nationwide cohort study found that children exposed to one course of antenatal corticosteroids were significantly more likely to have an increased risk of serious infection during the first 12 months of life. These findings suggest that before starting treatment, the long term risks of rare but serious infection associated with antenatal corticosteroids should be carefully weighed against the benefits in the perinatal period.
A Systematic Review and Meta-Analysis of Interventions to Promote Adjuvant Endocrine Therapy Adherence Among Breast Cancer Survivors
Authors: Emma E. Bright, Lauren B. Finkelstein, Madeline S. Nealis, Sarah R. Genung, Jordan Wrigley, Heng Chao J. Gu, Sarah J. Schmiege, Joanna J. Arch
Journal: Journal of Clinical Oncology (2023)

Adjuvant endocrine therapy (AET) adherence among breast cancer survivors is often suboptimal, leading to higher cancer recurrence and mortality. Intervention studies to promote AET adherence have burgeoned, more than doubling in number since this literature was last reviewed. The current aim is to provide an up-to-date systematic review and meta-analysis of interventions to enhance AET adherence and to identify strengths and limitations of existing interventions to inform future research and clinical care.
Exportin 1 inhibition prevents neuroendocrine transformation through SOX2 down-regulation in lung and prostate cancers
Authors: Alvaro Quintanal-Villalonga, Vidushi Durani, Amin Sabet, Esther Redin, Kenta Kawasaki, Moniquetta Shafer, Wouter R. Karthaus, Samir Zaidi, Yingqian A. Zhan, Parvathy Manoj, Harsha Sridhar, Nisargbhai S. Shah, Andrew Chow, Umesh K. Bhanot, Irina Linkov, Marina Asher, Helena A. Yu, Juan Qiu, Elisa de Stanchina, Radhika A. Patel, Colm Morrissey, Michael C. Haffner, Richard P. Koche, Charles L. Sawyers, Charles M. Rudin
Journal: Science Translational Medicine (2023)

In lung and prostate adenocarcinomas, neuroendocrine (NE) transformation to an aggressive derivative resembling small cell lung cancer (SCLC) is associated with poor prognosis. We previously described dependency of SCLC on the nuclear transporter exportin 1. Here, we explored the role of exportin 1 in NE transformation. We observed up-regulated exportin 1 in lung and prostate pretransformation adenocarcinomas. Exportin 1 was up-regulated after genetic inactivation of TP53 and RB1 in lung and prostate adenocarcinoma cell lines, accompanied by increased sensitivity to the exportin 1 inhibitor selinexor in vitro. Exportin 1 inhibition prevented NE transformation in different TP53/RB1-inactivated prostate adenocarcinoma xenograft models that acquire NE features upon treatment with the aromatase inhibitor enzalutamide and extended response to the EGFR inhibitor osimertinib in a lung cancer transformation patient-derived xenograft (PDX) model exhibiting combined adenocarcinoma/SCLC histology. Ectopic SOX2 expression restored the enzalutamide-promoted NE phenotype on adenocarcinoma-to-NE transformation xenograft models despite selinexor treatment. Selinexor sensitized NE-transformed lung and prostate small cell carcinoma PDXs to standard cytotoxics. Together, these data nominate exportin 1 inhibition as a potential therapeutic target to constrain lineage plasticity and prevent or treat NE transformation in lung and prostate adenocarcinoma.
Serum Proteomic Analysis of Peripartum Cardiomyopathy Reveals Distinctive Dysregulation of Inflammatory and Cholesterol Metabolism Pathways
Authors: Jana P. Lovell, Kevin Bermea, Jinsheng Yu, Sylvie Rousseau, Charles D. Cohen, Aashik Bhalodia, Marcelle Dina Zita, Richard D. Head, Roger S. Blumenthal, Rami Alharethi, Julie Damp, John Boehmer, Jeffrey Alexis, Dennis M. McNamara, Garima Sharma, Luigi Adamo, Dennis M. aaaMcNamara, James D. Fett, Jessica Pisarcik, Charles McTiernan, Karen Hanley-Yanez, John Gorcsan, Erik Schelbert, Rami Alharethi, Kismet Rasmusson, Kim Brunisholz, Amy Butler, Deborah Budge, A.G. Kfoury, Benjamin Horne, Joe Tuinei, Heather Brown, Julie Damp, Allen J. Naftilan, Jill Russell, Darla Freehardt, Eileen Hsich, Cynthia Oblak, Greg Ewald, Donna Whitehead, Jean Flanagan, Anne Platts, Uri Elkayam, Jorge Caro, Stephanie Mullin, Michael M. Givertz, M. Susan Anello, Navin Rajagopalan, David Booth, Tiffany Sandlin, Wendy Wijesiri, Leslie T. Cooper, Lori A. Blauwet, Joann Brunner, Mary Phelps, Ruth Kempf, Kalgi Modi, Tracy Norwood, Joan Briller, Decebal Sorin Griza, G. Michael Felker, Robb Kociol, Patricia Adams, Gretchen Wells, Vinay Thohan, Deborah Wesley-Farrington, Sandra Soots, Richard Sheppard, Caroline Michel, Nathalie Lapointe, Heather Nathaniel, Angela Kealey, Marc Semigran, Maureen Daher, John Boehmer, David Silber, Eric Popjes, Patricia Frey, Todd Nicklas, Jeffrey Alexis, Lori Caufield, John W. Thornton, Mindy Gentry, Vincent J.B. Robinson, Gyanendra K. Sharma, Joan Holloway, Maria Powell, David Markham, Mark Drazner, Lynn Fernandez, Mark Zucker, David A. Baran, Martin L. Gimovsky, Natalia Hochbaum, Bharati Patel, Laura Adams, Gautam Ramani, Stephen Gottlieb, Shawn Robinson, Stacy Fisher, Joanne Marshall, Jennifer Haythe, Donna Mancini, Rachel Bijou, Maryjane Farr, Marybeth Marks, Henry Arango, Biykem Bozkurt, Mariana Bolos, Paul Mather, Sharon Rubin, Raphael Bonita, Susan Eberwine, Hal Skopicki, Kathleen Stergiopoulos, Ellen McCathy-Santoro, Jennifer Intravaia, Elizabeth Maas, Jordan Safirstein, Audrey Kleet, Nancy Martinez, Christine Corpoin, Donna Hesari, Sandra Chaparro, Laura J. Hudson, Jalal K. Ghali, Zora Injic, Ilan S. Wittstein, Dennis M. McNamara, Karen Janosko, Charles McTiernan, Barry London, Karen Hanley-Yanez, John Gorcsan, Hidekazu Tanaka, Mathew Suffoletto, Randall C. Starling, Cynthia Oblak, Leslie T. Cooper, Annette McNallan, LuAnne Koenig, Paul Mather, Natalie Pierson, Sharon Rubin, Yanique Bell, Alicia Ervin, John Boehmer, Patricia Frey, Jeffrey Alexis, Janice Schrack, Pam LaDuke, Guillermo Torre-Amione, Jeannie Arredondo, Daniel F. Pauly, Pamela C. Smith, Richard Sheppard, Stephanie Fuoco, Ilan S. Wittstein, Elayne Breton, Vinay Thohan, Deborah Wesley, G. William Dec, Diane Cocca-Spofford, David W. Markham, Lynn Fernandez, Colleen Debes, Mark J. Zucker, Laura Adams, Peter Liu, Judith Renton, Jagat Narula, Byron Allen, Elizabeth Westberg
Journal: JACC Heart Failure (2023)
Tumor Microenvironment Modifications Induced by Afatinib in Squamous Cell Carcinoma of the Head and Neck: A Window-of-Opportunity Study (EORTC-90111–24111)
Authors: Simon P. Beyaert, Axelle E. Loriot, Nicolas D. Huyghe, Rose-Marie Goebbels, Antonella Mendola, Anne-Sophie Govaerts, Catherine Fortpied, Pamela Baldin, Lisa F. Licitra, Yassine Lalami, Paul M. Clement, Jean-Pascal H. Machiels, Sandra Schmitz
Journal: Clinical Cancer Research (2023)

Abstract Purpose: The EORTC-90111–24111 phase II window study evaluated afatinib versus no preoperative treatment in patients with primary squamous cell carcinoma of the head and neck (HNSCC). We investigated afatinib-induced tumor and microenvironment modifications by comparing pre- and posttreatment tumor biopsies. Patients and Methods: Thirty treatment-naïve patients with primary HNSCC were randomized. Twenty-five patients received afatinib for 14 days before surgery (40 mg 1×/day) and 5 patients were attributed to the control arm. Biopsies were taken at work-up and during surgery. Good quality RNA samples were used for omics analyses. The control arm was enlarged by samples coming from our previous similar window study. Results: IHC analyses of afatinib-treated tumor biopsies showed a decrease in pEGFR (P ≤ 0.05) and pERK (P ≤ 0.05); and an increase in CD3+ (P ≤ 0.01) and CD8+ (P ≤ 0.01) T-cell infiltration, and in CD3+ (P ≤ 0.05) T-cell density. RNA sequencing analyses of afatinib-treated tumor samples showed upregulation of inflammatory genes and increased expression scores of signatures predictive of response to programmed cell death protein 1 blockade (P ≤ 0.05). In posttreatment biopsies of afatinib-treated patients, two clusters were observed. Cluster 1 showed a higher expression of markers and gene sets implicated in epithelial-to-mesenchymal transition (EMT) and activation of cancer-associated fibroblasts (CAF) compared with cluster 2 and controls. Conclusions: Short-term treatment with afatinib in primary HNSCC induces CD3+ and CD8+ tumor infiltration and, in some patients, EMT and CAF activation. These results open perspectives to overcome resistance mechanisms to anti-HER therapy and to potentiate the activity of immune checkpoint inhibitors.
Racial and ethnic and socioeconomic disparities in childhood cancer incidence trends in the United States, 2000-2019
Authors: Pablo S Monterroso, Zhaoheng Li, Allison M Domingues, Jeannette M Sample, Erin L Marcotte
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Population-based surveillance of pediatric cancer incidence trends is critical to determine high-risk populations, drive hypothesis generation, and uncover etiologic heterogeneity. We provide a comprehensive update to the current understanding of pediatric cancer incidence trends by sex, race and ethnicity, and socioeconomic status (SES). Methods The Surveillance, Epidemiology, and End Results 22 data (2000-2019) was used to summarize age-adjusted incidence rates for children and adolescents aged 0-19 years at diagnosis. The annual percentage change (APC) and 95% confidence interval (CI) were estimated to evaluate incidence trends by sex, race and ethnicity, and SES overall and for cancer subtypes. Tests of statistical significance were 2-sided. Results Substantial variation was observed overall and for several histologic types in race and ethnicity– and SES–specific rates. Overall, we observed a statistically significant increase in incidence rates (APC = 0.8%, 95% CI = 0.6% to 1.1%). All race and ethnic groups saw an increase in incidence rates, with the largest occurring among non-Hispanic American Indian and Alaska Native children and adolescents (APC = 1.7%, 95% CI = 0.5% to 2.8%) and the smallest increase occurring among non-Hispanic White children and adolescents (APC = 0.7%, 95% CI = 0.5% to 1.0%). The lowest SES quintiles saw statistically significant increasing trends, while the highest quintile remained relatively stable (quintile 1 [Q1] APC = 1.6%, 95% CI = 0.6% to 2.6%; quintile 5 [Q5] APC = 0.3%, 95% CI = –0.1% to 0.7%). Conclusions Childhood cancer incidence is increasing overall and among every race and ethnic group. Variation by race and ethnicity and SES may enable hypothesis generation on drivers of disparities observed.
Harnessing Natural Killer Cells for Lung Cancer Therapy
Authors: Shoubao Ma, Michael A. Caligiuri, Jianhua Yu
Journal: Cancer Research (2023)

Abstract Lung cancer is the leading cause of cancer-related death worldwide. Although natural killer (NK) cells are garnering interest as a potential anticancer therapy because they selectively recognize and eliminate cancer cells, their use in treating solid tumors, including lung cancer, has been limited due to impediments to their efficacy, such as their limited ability to reach tumor tissues, the reduced antitumor activity of tumor-infiltrating NK cells, and the suppressive tumor microenvironment (TME). This comprehensive review provides an in-depth analysis of the cross-talk between the lung cancer TME and NK cells. We highlight the various mechanisms used by the TME to modulate NK-cell phenotypes and limit infiltration, explore the role of the TME in limiting the antitumor activity of NK cells, and discuss the current challenges and obstacles that hinder the success of NK-cell–based immunotherapy for lung cancer. Potential opportunities and promising strategies to address these challenges have been implemented or are being developed to optimize NK-cell–based immunotherapy for lung cancer. Through critical evaluation of existing literature and emerging trends, this review provides a comprehensive outlook on the future of NK-cell–based immunotherapy for treating lung cancer.